AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation
Advanced glycation end products (AGEs) are localized in macrophage-derived foam cells within atherosclerotic lesions, which could be associated with the increased risk of atherosclerotic cardiovascular disease under diabetic conditions. Although foam cell formation of macrophages has been shown to b...
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/23/9263 |
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| author | Hironori Yashima Michishige Terasaki Ami Sotokawauchi Takanori Matsui Yusaku Mori Tomomi Saito Naoya Osaka Hideki Kushima Munenori Hiromura Makoto Ohara Tomoyasu Fukui Sho-ichi Yamagishi |
| author_facet | Hironori Yashima Michishige Terasaki Ami Sotokawauchi Takanori Matsui Yusaku Mori Tomomi Saito Naoya Osaka Hideki Kushima Munenori Hiromura Makoto Ohara Tomoyasu Fukui Sho-ichi Yamagishi |
| author_sort | Hironori Yashima |
| collection | DOAJ |
| description | Advanced glycation end products (AGEs) are localized in macrophage-derived foam cells within atherosclerotic lesions, which could be associated with the increased risk of atherosclerotic cardiovascular disease under diabetic conditions. Although foam cell formation of macrophages has been shown to be enhanced by AGEs, the underlying molecular mechanism remains unclear. Since cyclin-dependent kinase 5 (Cdk5) is reported to modulate inflammatory responses in macrophages, we investigated whether Cdk5 could be involved in AGE-induced <i>CD36</i> gene expression and foam cell formation of macrophages. AGEs significantly increased Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and <i>Cdk5</i> and <i>CD36</i> gene expression in U937 human macrophages, all of which were inhibited by DNA aptamer raised against RAGE (RAGE-aptamer). <i>Cdk5</i> and <i>CD36</i> gene expression levels were correlated with each other. An antioxidant, <i>N</i>-acetyl-<span style="font-variant: small-caps;">l</span>-cysteine, mimicked the effects of RAGE-aptamer on AGE-exposed U937 cells. A selective inhibitor of Cdk5, (R)-DRF053, attenuated the AGE-induced Dil-ox-LDL uptake and <i>CD36</i> gene expression, whereas anti-CD36 antibody inhibited the Dil-ox-LDL uptake but not <i>Cdk5</i> gene expression. The present study suggests that AGEs may stimulate ox-LDL uptake into macrophages through the Cdk5–CD36 pathway via RAGE-mediated oxidative stress. |
| first_indexed | 2024-03-10T14:19:06Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:19:06Z |
| publishDate | 2020-12-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0aa9afc65a324aacb66d987d94480a8f2023-11-20T23:30:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012123926310.3390/ijms21239263AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress GenerationHironori Yashima0Michishige Terasaki1Ami Sotokawauchi2Takanori Matsui3Yusaku Mori4Tomomi Saito5Naoya Osaka6Hideki Kushima7Munenori Hiromura8Makoto Ohara9Tomoyasu Fukui10Sho-ichi Yamagishi11Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanDepartment of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanDepartment of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, JapanDepartment of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, JapanAnti-Glycation Research Section, Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanDepartment of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanDepartment of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanDepartment of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanDepartment of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanDepartment of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanDepartment of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanDepartment of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, JapanAdvanced glycation end products (AGEs) are localized in macrophage-derived foam cells within atherosclerotic lesions, which could be associated with the increased risk of atherosclerotic cardiovascular disease under diabetic conditions. Although foam cell formation of macrophages has been shown to be enhanced by AGEs, the underlying molecular mechanism remains unclear. Since cyclin-dependent kinase 5 (Cdk5) is reported to modulate inflammatory responses in macrophages, we investigated whether Cdk5 could be involved in AGE-induced <i>CD36</i> gene expression and foam cell formation of macrophages. AGEs significantly increased Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and <i>Cdk5</i> and <i>CD36</i> gene expression in U937 human macrophages, all of which were inhibited by DNA aptamer raised against RAGE (RAGE-aptamer). <i>Cdk5</i> and <i>CD36</i> gene expression levels were correlated with each other. An antioxidant, <i>N</i>-acetyl-<span style="font-variant: small-caps;">l</span>-cysteine, mimicked the effects of RAGE-aptamer on AGE-exposed U937 cells. A selective inhibitor of Cdk5, (R)-DRF053, attenuated the AGE-induced Dil-ox-LDL uptake and <i>CD36</i> gene expression, whereas anti-CD36 antibody inhibited the Dil-ox-LDL uptake but not <i>Cdk5</i> gene expression. The present study suggests that AGEs may stimulate ox-LDL uptake into macrophages through the Cdk5–CD36 pathway via RAGE-mediated oxidative stress.https://www.mdpi.com/1422-0067/21/23/9263AGEsCdk5CD36RAGE-aptamermacrophages |
| spellingShingle | Hironori Yashima Michishige Terasaki Ami Sotokawauchi Takanori Matsui Yusaku Mori Tomomi Saito Naoya Osaka Hideki Kushima Munenori Hiromura Makoto Ohara Tomoyasu Fukui Sho-ichi Yamagishi AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation International Journal of Molecular Sciences AGEs Cdk5 CD36 RAGE-aptamer macrophages |
| title | AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation |
| title_full | AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation |
| title_fullStr | AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation |
| title_full_unstemmed | AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation |
| title_short | AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation |
| title_sort | age rage axis stimulates oxidized ldl uptake into macrophages through cyclin dependent kinase 5 cd36 pathway via oxidative stress generation |
| topic | AGEs Cdk5 CD36 RAGE-aptamer macrophages |
| url | https://www.mdpi.com/1422-0067/21/23/9263 |
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